RESUMO
The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-dependent and quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess.
Assuntos
Receptor de Insulina/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Animais , Linhagem Celular , Meios de Cultura , Humanos , Concentração de Íons de Hidrogênio , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênese Sítio-Dirigida , Fosforilação , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Ratos , Receptor de Insulina/genética , Proteínas Recombinantes de Fusão/genética , Transdução de Sinais , Bicarbonato de Sódio/farmacologia , Bicarbonato de Sódio/urina , Xenopus laevisRESUMO
Weak neurotoxins belong to the superfamily of three-finger toxins from snake venoms. In general, weak toxins have a low toxicity and, contrary to other three-finger toxins, their molecular targets are not well characterized: in vitro tests indicate that these may be nicotinic acetylcholine receptors. Here, we report the influence of intraperitoneal and intravenous injections of weak neurotoxin from Naja kaouthia venom on mouse behaviour. Dose-dependent suppression of orientation-exploration and locomotion activities as well as relatively weak neurotropic effects of weak neurotoxin were observed. The myorelaxation effect suggests a weak antagonistic activity against muscle-type nicotinic acetylcholine receptors. Neurotoxic effects of weak neurotoxin were related to its influence on peripheral nervous system. The symptomatology of the intoxication was shown to resemble that of muscarinic agonists. Our data suggest that, in addition to interaction with nicotinic acetylcholine receptors observed earlier in vitro, weak neurotoxin interacts in vivo with some other molecular targets. The results of behavioural experiments are in accord with the pharmacological profile of weak neurotoxin effects on haemodynamics in mice and rat indicating the involvement of both nicotinic and muscarinic acetylcholine receptors.
Assuntos
Comportamento Animal/efeitos dos fármacos , Proteínas Neurotóxicas de Elapídeos/toxicidade , Síndromes Neurotóxicas/fisiopatologia , Neurotoxinas/toxicidade , Estimulação Acústica , Animais , Cromatografia Líquida de Alta Pressão , Proteínas Neurotóxicas de Elapídeos/administração & dosagem , Proteínas Neurotóxicas de Elapídeos/isolamento & purificação , Defecação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Neurotoxinas/administração & dosagem , Neurotoxinas/isolamento & purificação , Tempo de Reação/efeitos dos fármacos , Insuficiência Respiratória/induzido quimicamente , Salivação/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Sensação Térmica/efeitos dos fármacos , Fatores de TempoRESUMO
Recent in vitro studies of weak neurotoxins from snake venoms have demonstrated their ability to interact with both muscle-type and neuronal alpha7 nicotinic acetylcholine receptors (nAChR). However, the biological activity in vivo of weak neurotoxins remains largely unknown. We have studied the influence of weak neurotoxin (WTX) from the venom of cobra Naja kaouthia on arterial blood pressure (BP) and heart rate (HR) in rats and mice. It was found that intravenous injection of WTX induced a dose-dependent decrease in BP and an increase in HR in both species, the rats being more sensitive to WTX. Application of WTX following blockade of nAChRs or muscarinic acetylcholine receptors (mAChR) by hexamethonium or atropine, respectively, showed that both nAChRs and mAChRs are involved in the haemodynamic effects of WTX. Blockade of either nAChRs or mAChRs affected WTX action differently in rats and mice, thus reflecting interspecies differences in haemodynamic regulation.
